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p53 dynamics vary between tissues and are linked with radiation sensitivity

Author

Listed:
  • Jacob Stewart-Ornstein

    (Blavatnik Institute at Harvard Medical School
    University of Pittsburgh Medical School)

  • Yoshiko Iwamoto

    (Massachusetts General Hospital)

  • Miles A. Miller

    (Massachusetts General Hospital)

  • Mark A. Prytyskach

    (Massachusetts General Hospital)

  • Stephane Ferretti

    (Novartis Institutes for Biomedical Research)

  • Philipp Holzer

    (Novartis Institutes for Biomedical Research)

  • Joerg Kallen

    (Novartis Institutes for Biomedical Research)

  • Pascal Furet

    (Novartis Institutes for Biomedical Research)

  • Ashwini Jambhekar

    (Blavatnik Institute at Harvard Medical School)

  • William C. Forrester

    (Chemical Biology and Therapeutics, Novartis Institutes for Biomedical Research)

  • Ralph Weissleder

    (Blavatnik Institute at Harvard Medical School
    Massachusetts General Hospital)

  • Galit Lahav

    (Blavatnik Institute at Harvard Medical School)

Abstract

Radiation sensitivity varies greatly between tissues. The transcription factor p53 mediates the response to radiation; however, the abundance of p53 protein does not correlate well with the extent of radiosensitivity across tissues. Given recent studies showing that the temporal dynamics of p53 influence the fate of cultured cells in response to irradiation, we set out to determine the dynamic behavior of p53 and its impact on radiation sensitivity in vivo. We find that radiosensitive tissues show prolonged p53 signaling after radiation, while more resistant tissues show transient p53 activation. Sustaining p53 using a small molecule (NMI801) that inhibits Mdm2, a negative regulator of p53, reduced viability in cell culture and suppressed tumor growth. Our work proposes a mechanism for the control of radiation sensitivity and suggests tools to alter the dynamics of p53 to enhance tumor clearance. Similar approaches can be used to enhance killing of cancer cells or reduce toxicity in normal tissues following genotoxic therapies.

Suggested Citation

  • Jacob Stewart-Ornstein & Yoshiko Iwamoto & Miles A. Miller & Mark A. Prytyskach & Stephane Ferretti & Philipp Holzer & Joerg Kallen & Pascal Furet & Ashwini Jambhekar & William C. Forrester & Ralph We, 2021. "p53 dynamics vary between tissues and are linked with radiation sensitivity," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21145-z
    DOI: 10.1038/s41467-021-21145-z
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    Cited by:

    1. Ai Tamura & Kazuyuki Yamagata & Takashi Kono & Masanori Fujimoto & Takahiro Fuchigami & Motoi Nishimura & Masataka Yokoyama & Akitoshi Nakayama & Naoko Hashimoto & Ikki Sakuma & Nobuyuki Mitsukawa & Y, 2025. "p53-inducible lncRNA LOC644656 causes genotoxic stress-induced stem cell maldifferentiation and cancer chemoresistance," Nature Communications, Nature, vol. 16(1), pages 1-22, December.
    2. Ross J. Hill & Nazareno Bona & Job Smink & Hannah K. Webb & Alastair Crisp & Juan I. Garaycoechea & Gerry P. Crossan, 2024. "p53 regulates diverse tissue-specific outcomes to endogenous DNA damage in mice," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    3. Demirkıran, Gökhan, 2022. "Piecewise parametric chaotic model of p53 network based on the identified unifying framework of divergent p53 dynamics," Chaos, Solitons & Fractals, Elsevier, vol. 160(C).

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